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Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas

Oncogene volume 23, pages 5901–5911 (2004)Cite this article

Abstract

Hepatoblastoma is one of the most common malignant liver tumors in young children. Recent evidences have suggested that the abnormalities in Wnt signaling pathway, as seen in frequent mutation of the β-catenin gene, may play a role in the genesis of hepatoblastoma. However, the precise mechanism to cause the tumor has been elusive. To identify novel hepatoblastoma-related genes for unveiling the molecular mechanism of the tumorigenesis, a large-scale cloning of cDNAs and differential screening of their expression between hepatoblastomas and the corresponding normal livers were performed. We constructed four full-length-enriched cDNA libraries using an oligo-capping method from the primary tissues which included two hepatoblastomas with high levels of alpha-fetoprotein (AFP), a hepatoblastoma without production of AFP, and a normal liver tissue corresponded to the tumor. Among the 10 431 cDNAs randomly picked up and successfully sequenced, 847 (8.1%) were the genes with unknown function. Of interest, the expression profile among the two subsets of hepatoblastoma and a normal liver was extremely different. A semiquantitative RT–PCR analysis showed that 86 out of 1188 genes tested were differentially expressed between hepatoblastomas and the corresponding normal livers, but that only 11 of those were expressed at high levels in the tumors. Notably, PLK1 oncogene was expressed at very high levels in hepatoblastomas as compared to the normal infant's livers. Quantitative real-time RT–PCR analysis for the PLK1 mRNA levels in 74 primary hepatoblastomas and 29 corresponding nontumorous livers indicated that the patients with hepatoblastoma with high expression of PLK1 represented significantly poorer outcome than those with its low expression (5-year survival rate: 55.9 vs 87.0%, respectively, p=0.042), suggesting that the level of PLK1 expression is a novel marker to predict the prognosis of hepatoblastoma. Thus, the differentially expressed genes we have identified may become a useful tool to develop new diagnostic as well as therapeutic strategies of hepatoblastoma.

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Acknowledgements

We are grateful to Shigeru Sakiyama and Toshinori Ozaki for critical reading of the manuscript, and Yoko Nakamura and Aiko Morohashi for experimental support. We thank Eriko Isogai, Naoko Sugimitsu, and Yuki Nakamura for preparing RNA and sequencing analysis, and Natsue Kitabayashi, Emiko Kojima, Emi Goto, and Hisae Murakami for technical assistance. We also thank the hospitals and institutions collaborating with the Japanese Study Group for Pediatric Liver Tumor (JPLT) for providing surgical specimens. This work was supported in part by the fund from Hisamitsu Pharmaceutical Company and a grant-in-aid for Scientific Research on Priority Areas (C) ‘Medical Genome Science’ from the Ministry of Education, Culture, Sports, Science, and Technology of Japan.

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Authors and Affiliations

  1. Division of Biochemistry, Chiba Cancer Center Research Institute, Chiba, 260-8717, Japan

    Shin-ichi Yamada, Miki Ohira, Kiyohiro Ando, Hajime Takayasu & Akira Nakagawara

  2. Japanese Study Group for Pediatric Liver Tumor, Japan

    Hiroshi Horie, Tadashi Matsunaga, Eiso Hiyama, Yutaka Hayashi, Hisami Ando, Sachiyo Suita, Michio Kaneko, Fumiaki Sasaki, Kohei Hashizume, Naomi Ohnuma & Akira Nakagawara

  3. Human Genome Center, Institute of Medical Science, University of Tokyo, Tokyo, 108-8639, Japan

    Yutaka Suzuki & Sumio Sugano

  4. Hisamitsu Pharmaceutical Co. Inc., Tokyo, 100-6221, Japan

    Takahiro Hirata & Takeshi Goto

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Yamada, Si., Ohira, M., Horie, H. et al. Expression profiling and differential screening between hepatoblastomas and the corresponding normal livers: identification of high expression of the PLK1 oncogene as a poor-prognostic indicator of hepatoblastomas. Oncogene 23, 5901–5911 (2004). https://doi.org/10.1038/sj.onc.1207782

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